Activation of the cardiac ATP-sensitive K⁺ channel by ER-001533, a newly synthesized vasorelaxant

Effects of ER-001533 (ER), a newly synthesized vasorelaxant, on the membrane currents were examined in single ventricular cells of guinea pigs. The patch-clamp technique was used in the 'whole-cell' and 'inside-out' patch configurations. In the whole-cell clamp condition, ER induced a time- independent K⁺-dominant current, which was inhibited by glibenclamide (1-3 μM), suggesting that ER activated the cardiac ATP-sensitive K⁺ channel (K(ATP)). To elucidate the mechanism of ER-mediated K(ATP) channel activation, the drug was applied to the inside-out patches before and after channel 'run-down.' Since nucleotide diphosphates could induce the channel openings after complete run-down, effects of the drug on the nucleotide diphosphate-induced channel openings were also examined. Before run-down, ER activated the K(ATP) channel only in the presence of ATP. ER shifted the relation between [ATP](i) and the channel activity to the right in a concentration-dependent fashion without a significant alteration of the slope. After channel run-down, ER did not affect the channel openings either in the absence or in the presence of UDP. However, ER could relieve the ATP- γ-S inhibition of the UDP-induced channel openings. Thus, we conclude that ER antagonizes the inhibitory effect of ATP on the K(ATP) channel in a competitive manner, thereby enhancing the channel openings.